Methoxsalen

Methoxsalen
Clinical data
Trade names	Oxsoralen-Ultra, Uvadex, 8-mop, Oxsoralen
AHFS/Drugs.com	Consumer Drug Information
ATC code	D05AD02 (WHO) D05BA02 (WHO);
Pharmacokinetic data
Elimination half-life	~2 hours
Identifiers
	IUPAC name 9-methoxy-7H-furo[3,2-g]chromen-7-one;
CAS Number	298-81-7 ;
PubChem CID	4114;
DrugBank	DB00553 ;
ChemSpider	3971 ;
UNII	U4VJ29L7BQ;
KEGG	D00139 ;
ChEBI	CHEBI:18358 ;
ChEMBL	CHEMBL416 ;
NIAID ChemDB	001590;
ECHA InfoCard	100.005.516
Chemical and physical data
Formula	C12H8O4
Molar mass	216.19 g/mol
3D model (JSmol)	Interactive image;
	SMILES COc1c2c(ccc(=O)o2)cc3c1occ3;
	InChI InChI=1S/C12H8O4/c1-14-12-10-8(4-5-15-10)6-7-2-3-9(13)16-11(7)12/h2-6H,1H3 ; Key:QXKHYNVANLEOEG-UHFFFAOYSA-N ;
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Methoxsalen (also called xanthotoxin, marketed under the trade names Oxsoralen, Deltasoralen, Meladinine) is a drug used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to UVA light from lamps or sunlight. Methoxsalen modifies the way skin cells receive the UVA radiation, allegedly clearing up the disease. The dosage comes in 10 mg tablets, which are taken in the amount of 30 mg 75 minutes before a PUVA (psoralen + UVA) light treatment. Levels of individual patient PUVA exposure were originally determined using the Fitzpatrick scale. The scale was developed after patients demonstrated symptoms of phototoxicity after oral ingestion of Methoxsalen followed by PUVA therapy. Chemically, methoxsalen belongs to a class of organic natural molecules known as furanocoumarins. They consist of coumarin annulated with furan. It can also be injected and used topically.

Natural sources

In 1970, Nielsen extracted methoxsalen (8-methoxypsoralen) from 4 species of the Heracleum genus in the Apiaceae family,^[1]^[2] including Heracleum mantegazzianum and Heracleum sphondylium. An additional 32 species of the Heracleum genus were found to contain bergapten (5-methoxypsoralen) or other furanocoumarins.

Biosynthesis

The biosynthetic pathway is a combination of the shikimate pathway, which produces umbelliferone, and the mevalonate pathway.

Synthesis of umbelliferone

Umbelliferone

Umbelliferone is a phenylpropanoid and as such is synthesized from L-phenylalanine, which in turn is produced via the shikimate pathway. Phenylalanine is lysated into cinnamic acid, followed by hydroxylation by cinnamate 4-hydroxylase to yield 4-coumaric acid. The 4-coumaric acid is again hydroxylated by cinnamate/coumarate 2-hydroxylase to yield 2,4-dihydroxy-cinnamic acid (umbellic acid) followed by a bond rotation of the unsaturated bond adjacent to the carboxylic acid group. Finally an intramolecular attack from the hydroxyl group of C2' to the carboxylic acid group closes the ring and forms the lactone umbelliferone.

Synthesis of methoxsalen

Dimethylallyl pyrophosphate

The biosynthetic route then continues with the activation of dimethylallyl pyrophosphate (DMAPP), produced via the mevalonate pathway, to form a carbo-cation via the cleavage of the diphosphates. Once activated, the enzyme umbelliferone 6-prenyltransferase catalyzes a C-alkylation between DMAPP and umbelliferone at the activated position ortho to the phenol, yielding demethylsuberosin. This is then followed by a hydroxylation catalyzed by the enzyme marmesin synthase to yield marmesin. Another hydroxylation is catalyzed by psoralen synthase to yield psoralen. A third hydroxylation by the enzyme psoralen 8-monooxygenase yields xanthotoxol which is followed by a methylation via the enzyme xanthotoxol O-methyltransferase and S-adenosyl methionine to yield methoxsalen.^[3]

Risks and side effects

Patients with high blood pressure or a history of liver problems are at risk for inflammation and irreparable damage to both liver and skin. The eyes must be protected from UVA radiation. Side effects include nausea, headaches, dizziness, and in rare cases insomnia.

Methoxsalen has also been classified as an IARC Group 1 carcinogen (known to cause cancer) but is only cancerous when combined with light - UVA radiation.^[4]

Cultural aspects

Author John Howard Griffin (1920–1980) used the chemical to darken his skin in order to investigate racial segregation in the American South. He wrote the book Black Like Me (1961) about his experiences.^[5]

References

↑ Nielsen, B. E. (1970). Coumarins of Umbelliferous plants. Copenhagen: Royal Danish School of Pharmacy. Cited by Mitchell and Rook (1979).
↑ Mitchell, John; Rook, Arthur (1979). Botanical Dermatology: Plants and Plant Products Injurious to the Skin. Vancouver: Greengrass. pp. 692–699.
↑ Dewick, P. M. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). John Wiley & Sons. pp. 161, 164–165.
↑ http://www.cancer.org/cancer/cancercauses/othercarcinogens/generalinformationaboutcarcinogens/known-and-probable-human-carcinogens
↑ Dead Like Me on snopes.com

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[1] Nielsen, B. E. (1970). Coumarins of Umbelliferous plants. Copenhagen: Royal Danish School of Pharmacy. Cited by Mitchell and Rook (1979).

[2] Mitchell, John; Rook, Arthur (1979). Botanical Dermatology: Plants and Plant Products Injurious to the Skin. Vancouver: Greengrass. pp. 692–699.

[3] Dewick, P. M. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). John Wiley & Sons. pp. 161, 164–165.

[4] ttp://www.cancer.org/cancer/cancercauses/othercarcinogens/generalinformationaboutcarcinogens/known-and-probable-human-carcinogens

[5] Dead Like Me on snopes.com